Project Summary Ventricular tachyarrhythmias are a principal cause of sudden cardiac death (SCD). While altered mechanical loading leading to hypertrophy and decompensated heart failure is one of the most powerful risk factors for fatal ventricular arrhythmias, the mechanisms that link mechanical to electrical dysfunction in the heart remain poorly understood. Consequently, SCD remains a major unresolved public health problem. The applicants mentor recently reported that ventricular electrical remodeling (VER), a persistent change in the electrophysiological properties of ventricular myocardium in response a change in activation sequence, is triggered by local mechanical stretch via a mechano-electrical feedback mechanism. Preliminary data from his laboratory revealed significant expression changes in the Gq/11-protein coupled mechanoreceptor pathway in high-strain myocardium from paced canine hearts. Considering the prominent roles of this pathway in cardiac mechanotransduction and pressure-overload hypertrophy, it is an ideal candidate to explain VER. The applicant hypothesizes that myocardial stretch causes VER and arrhythmias via enhanced Gq/11 activation. In his current position at Case Western Reserve University, he engineered a zebrafish whole-heart stretch system that combines high-precision stretch and high-resolution electrophysiology with high-throughput gene manipulation in an intact vertebrate heart. Ventricles from wild-type and genetically modified zebrafish embryo hearts are stretched during field-pacing for several hours via attached 10-micrometer-diameter thin carbon fibers to induce persistent VER. Following stretch, VER is determined using high-resolution fluorescence imaging. The applicants preliminary data show that his zebrafish model reproduces the key electrophysiological phenotypes of his mentors canine model of VER. The applicant will use his zebrafish VER model to determine (1) the key biomechanical and bioelectrical conditions that induce VER, (2) how stretch-induced VER enhances the susceptibility of the heart to arrhythmias and (3) the molecular signaling mechanisms that cause stretch-induced VER. These studies will help identify new therapeutic targets for preventing and treating VER and associated arrhythmias in patients with heart disease. Support for this project via a K99/R00 award would play a pivotal and requisite role in the candidates career development. His immediate goals are: (1) to solidify his research experience through additional intensive mentorship, technical training and broad intellectual development that will result directly from this proposal. The applicant has considerable experience in biophysics and experimental model development, but requires additional training in molecular and integrative biology to develop an independent academic career in cardiovascular biology. (2) to successfully obtain R01 funding by the end of the 5-year award period. A highly structured career development plan is an intrinsic component of this proposal and is designed to greatly enhance the accomplishment of the candidates long-term career goal: to establish a vibrant, independently funded, interdisciplinary research program that combines biomedical engineering, high-throughput genetics and high-resolution electrophysiology to study the molecular mechanisms of cardiac arrhythmias.